Predictors of Youth-Onset Type 2 Diabetes: UAB Clinical Center

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Minority youth are at elevated risk for type 2 diabetes (T2D) relative to non-Hispanic whites (NHW), with African-Americans (AA) and Hispanic-Americans (HA) showing the greatest increase in prevalence since 2000. Our overarching hypothesis is that underlying genetic differences in minority children interact with environmental factors in an adverse manner to increase risk for T2D. For example, the elevated beta-cell responsiveness and reduced hepatic insulin extraction exhibited by AA may increase risk for obesity and beta- cell dysfunction in the context of a diet high in sugar and processed starches. HA have both a genetic predisposition to fatty liver, due to a mutation in the carbohydrate-responsive PNPLA3 gene, and a genetic impairment in the ability to expand peripheral adipose tissue. In the context of weight gain and a high- sugar/processed carbohydrate diet, these genetic factors may increase risk for insulin resistance. The global purpose of RFA-DK-21-002 is to identify factors that predict conversion to T2D, and that disproportionately predispose minority youth to T2D. With our “University of Alabama at Birmingham (UAB) Clinical Center,” we propose to recruit, phenotype, and follow for 5 years 100 at-risk youth aged 8-16 yr without T2D at baseline comprised primarily of AA children with extreme obesity. Our team excels in assessment of insulin sensitivity and beta-cell function; assessment of body composition and body fat distribution; evaluation of the intrauterine environment; and conducting longitudinal cohort studies with high retention. Published data indicate that the greatest risk factors for pediatric T2D are extreme obesity (BMI z score > 2.5), impaired glucose tolerance (2-h glucose >140 mg/dL and <200 mg/dL), weight gain, and family or maternal/gestational history of diabetes. We will assess all of these variables with annual testing visits that will include an oral glucose tolerance test and dual-energy-X-ray absorptiometry (DXA) for body composition and fat distribution. In addition, we will collect genetic material for assessment of targeted SNPs with known association to T2D risk, and we will assess environmental factors such as psychosocial variables and diet. Sera/plasma will be archived for future metabolomics. Prediction models will be developed for incident T2D, as well as for prevalent and incident IGT, using suites of anthropometric/demographic, phenotypic, and genotypic variables. We hypothesize that ethnicity/race will not be statistically related to incident T2D when accounting for genotypic and/or phenotypic factors that affect risk for T2D, and their potential interaction with environmental factors. Results from this study will identify the genetic underpinnings of the phenotypic and anthropometric/familial factors that associate with, and reflect the pathophysiology of, IGT and T2D, and will determine whether these determinants differ with ethnicity/race. As such, the results of this study will identify targets for intervention, and markers for monitoring intervention effectiveness, that can be utilized in subsequent intervention studies.